Novel compositions of eprosartan

ABSTRACT

This invention relates to a novel composition comprising eprosartan, or a salt, solvate, or hydrate thereof, in particulate form, a process for its production and methods of using the composition to block angiotensin II receptors and to treat hypertension, congestive heart failure and renal failure.

FIELD OF THE INVENTION

[0001] This invention relates to novel compositions of(E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionicacid [eprosartan] or its methanesulfonate salt [eprosartan mesylatel],and to the use of such compositions in therapy to block angiotensin II(AII) receptors and in the treatment of hypertension, congestive heartfailure and renal failure.

BACKGROUND OF THE INVENTION

[0002] The compound,(E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic,is known by the name “eprosartan” and is the subject of U.S. Pat. No.5,185,351 (the '351 patent), issued Feb. 9, 1993. This patent disclosesa process for making the anhydrous form of(E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionicacid and its methanesulfonate salt. Additionally, the '351 patentdiscloses conventional techniques for formulating(E)-α-[2-n-butyl-1[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionicacid. Eprosartan mesylate has the following structure:

[0003] This compound is claimed to have utility in blocking angiotensinII receptors and to be useful in the treatment of hypertension,congestive heart failure and renal failure.

[0004] It is known that pharmaceutically active compounds may besubjected to milling procedures to obtain a particle size appropriatefor tablet formation and for other formulation types. Air jet millingand fluid energy milling (micronising) have been favoured because of thereduced risk from introducing contamination from mill materials.However, wet milling processes have been proposed for preparation offinely divided particles for pharmaceutical use, for example see U.S.Pat. No. 5,145,684. This patent discloses a wet milling procedure toproduce particles of a crystalline drug substance having a surfacemodifier adsorbed on the surface thereof in an amount sufficient tomaintain an effective average particle size of less than about 400 nm.This particulate composition as a stable suspension is said to provideimproved bioavailability for poorly water soluble compounds.

[0005] According to the instant invention, it has been found thateprosartan, or its salts, solvates, or hydrates, can be formulated innovel compositions that have a 2-5 fold enhanced therapeutic activityover that of conventionally-prepared immediate release tabletformulations of the same compound. These novel compositions haveenhanced bioavailability.

SUMMARY OF THE INVENTION

[0006] The present invention is based on the finding that(E)-α-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionicacid, or its salt forms, such as the mesylate, have enhancedbioavailability in certain compositions of controlled particle size.Anhydrous eprosartan, or its salts, or its solvates or hydrates, may beused in the compositions of the instant invention.

[0007] The present invention provides novel compositions comprisingeprosartan, or a salt, solvate, or hydrate thereof, in particulate form,said composition having a particle size distribution such that themedian value of the volume mean diameter is within the range of from 450to 700 nm.

[0008] This invention also provides a process or a method of producingsuch compositions in a reproducible manner for the treatment of diseasesin which blockade of angiotensin II receptors is indicated, for example,in the treatment of hypertension, congestive heart failure and renalfailure.

DESCRIPTION OF THE INVENTION

[0009] According to the present invention, compositions comprisingeprosartan, or its salt, are provided in particulate form, such asimmediate release (IR) capsules and immediate release/delayed release/modified release tablets. The compositions are prepared using a processthat involves a wet milling step in order to produce a particle sizedistribution of eprosartan, or its salt, with a volume average mediandiameter in the range of 450-700 nm. The particulate suspension, thusproduced, is spray dried using a spray dryer or granulated using a fluidbed granulator. Compositions are prepared by admixture and, thus, theyare suitably adapted for oral, parenteral or pulmonary administration.The compositions may be in the form of tablets, capsules,reconstitutable powders or suppositories. Orally administrablecompositions are preferred, in particular shaped oral compositions,since they are more convenient for mass therapy.

[0010] To assist in further processing, that is the preparation ofpharmaceutical compositions for therapeutic use, such as capsules andtablets, the wet milling of eprosartan, or its salt, takes place in anaqueous medium containing one or more pharmaceutically acceptablewater-soluble carriers suitable for spray drying. The aqueous suspensionmay optionally contain a surfactant to maintain the particles insuspension until administration of the pharmaceutical formulation to apatient. Pharmaceutically acceptable excipients most suitable forspray-drying are water soluble hydroxypropylmethyl cellulose, a binder,and mannitol. but other binders, such as polyvinylpyrrolidone (PVP),hydroxypropyl cellulose (HPC), and methyl cellulose, or othercarbohydrates, such as sucrose, sorbitol, lactose, lactitol and xylitoland starch may also be used as a carrier.

[0011] In the aqueous medium to be subjected to the milling, eprosartan,or its salt, may be present from about 10 to about 40% w/w. In practice,20% w/w drug loading provides an effective compromise between the desirefor a high throughput and short milling times.

[0012] The amount of the primary carrier, such as hydroxypropylmethylcellulose (HPMC), may vary from about 2 to about 20% w/w of thecomposition to be milled. The secondary carrier, such as mannitol, mayalso be added to the suspension prior to milling or dissolved in themilled suspension prior to spray drying. Preferably, the total amount ofthe soluble carrier(s) does not exceed 100% by weight of eprosartan, orits salt, to be processed. For an eprosartan loading of about 20% w/w,an amount of HPMC from about 4 to 12% w/w has been found to beeffective, and an amount of about 6% w/w is preferred.

[0013] The amount of surfactant/glidant, if present, may be varied fromabout 0.1 to about 0.4% w/w of the aqueous medium. Preferably, it ispresent at about 1% by weight of eprosartan, or its salt. Suitablesurfactants are sodium laurel sulphate and tween 80, while suitableglidents are silicon dioxide and talc.

[0014] The compositions of this invention are most suitably prepared bywet milling eprosartan, or its salt, preferably using a bead mill suchas Premier HML Laboratory Supermill manufactured by Premier MillCorporation, Reading, Pa. The milling medium consists of zirconium oxidebeads. Bead mills manufactured by others such as Dena Mill by DenaSystems BK Ltd., Barnsley, England, can be used for wet millingeprosartan, or its salt. The particle size distributions of thesuspension formulations were determined using a Malvern laserdiffraction unit, Master Sizer S Model S4700, from Malvern InstrumentsLtd., Malvern, England. Any other laser diffraction particle sizer withsufficient sensitivity and resolution for nanoparticulates can be used.The particles of eprosartan, or its salt, are typically present with notless than 50% of the particles having a volume average diameter of 1000nm or below. In a preferred embodiment of the invention, the volumeaveraged median diameter is in the range of 450 to 700 nm. In thismedian range, effective compositions are obtained when 90% of theparticles have a volume averaged diameter of 1200 nm or below.

[0015] Using the milling beads and aqueous carrier system describedabove, a composition having the preferred particle size distribution maybe obtained surprisingly quickly, for example, after milling 2.5 kgsuspension in the mill for an hour. Increasing milling time, forexample, by fivefold, enables the largest particles to be reduced sothat at least 90% of particles have a volume average diameter of lessthan 1000 nm. However, the effect on the median value is marginal, solonger milling times are not cost effective.

[0016] Spray drying/fluid bed granulation of milled compositions iscarried out most suitably using a spray dryer such as Yamato GA-32 SprayDryer [Yamato Scientific America Inc., Orangeburg, N.Y.], or a fluid bedgranulator, such as Glatt fluid bed granulator.

[0017] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers and diluents (tableting or compression aids),lubricants, disintegrants, colorants, flavourings, and wetting agents.The tablets may be coated according to techniques well known in the art.

[0018] Suitable binders include polyvinlpyrrolidone (PVP),hydroxypropylmethyl cellulose and pregelatinized starch (Starch 1551).Suitable fillers include microcrystalline cellulose mannitol, lactoseand other similar agents. Suitable disintegrants include superdisintegrants such as cross linked polyvinylpyrrolidone (CrospovidoneXL), sodium starch glycolate (Explotab) and croscarmellose sodium(Ac-Di-Sol). Suitable lubricants include stearic acid and magnesiumstearate.

[0019] These solid oral compositions may be prepared by conventionalmethods of blending, filling, tableting, or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, well known in the art.

[0020] Oral formulations also include conventional controlled releaseformulations, such as tablets or pellets, beads or granules, having asustained release or an enteric coating, or otherwise modified tocontrol the release of the active compound, for example by the inclusionof gel forming polymers or matrix forming waxes.

[0021] Advantageously, a surfactant or wetting agent may be included inthe composition to facilitate uniform distribution of the compound ofthe invention.

[0022] Thus, the present invention provides a novel composition whichcomprises eprosartan, or its salts, solvates, or hydrates. Thecomposition is adapted for oral administration. The composition ispresented as a unit dose. Such a composition is taken preferably from 1to 2 times daily. The preferred unit dosage forms include tablets orcapsules. The compositions of this invention may be formulated byconventional methods of admixture such as blending, filling andcompressing. Suitable pharmaceutically acceptable carriers for use inthis invention include diluents, fillers, binders and disintegrants.

[0023] Eprosartan, or its salts, solvates, or hydrates, may beco-administered with other pharmaceutically active compounds, forexample, in physical combination or by sequential administration.Conveniently, the compound of this invention and the other activecompound are formulated in a pharmaceutical composition. Thus, thisinvention also relates to pharmaceutical compositions comprisingeprosartan, or its salts, solvates, or hydrates, a pharmaceuticallyacceptable carrier, and a second pharmaceutically active compoundselected from the group consisting of a diuretic, a calcium channelblocker, a β-adrenoceptor blocker, a renin inhibitor, and an angiotensinconverting enzyme inhibitor. Examples of compounds which may be includedin pharmaceutical compositions in combination with eprosartan, or itssalts, solvates, or hydrates, are diuretics, particularly a thiazidediuretic, such as hydrochlorothiazide, or a loop diuretic, such asfurosemide, calcium channel blockers, particularly dihydropyridineantagonists, such as nifedipine, β-adrenoceptor blockers, such aspropranolol, renin inhibitors, such as enalkinen, and angiotensinconverting enzyme inhibitors. such as captopril or enalapril.

[0024] No unacceptable toxicological effects are expected wheneprosartan, or its salts, solvates, or hydrates is administered inaccordance with the present invention.

[0025] Eprosartan, or its salts, solvates, or hydrates is useful fortreating diseases in which blockade of the angiotensin II receptor wouldbe beneficial. Preferably, this compound is used alone or in combinationwith said second pharmaceutically active compounds in the treatment ofhypertension, congestive heart failure and renal failure. Additionally,eprosartan, or its salts, solvates, or hydrates, is of value in thetreatment of left ventricular hypertrophy regression, diabeticnephropathy, diabetic retinopathy, mascular degeneration, haemorrhagicstroke, primary and secondary prevention of infarction, prevention ofatheroma progression and the regression of atheroma, prevention ofrestinosis after angioplasty or bypass surgery, improving cognitivefunction, angina, glaucoma, and CNS disorders, such as anxiety.

[0026] The following examples are illustrative of the instant invention.These examples are not intended to limit the scope of this invention asdefined hereinabove and as claimed hereinbelow.

Examples of Nanoparticulate Suspensions

[0027] Suspensions (refer to Table 1 for formulation details) wereprepared by dispersing hydroxypropylmethylcellulose (HPMC) in purifiedwater, using a suitable mixer and stored overnight to hydrate. The drugsubstance was dispersed using a homogenizer and mixing continued untilno drug agglomerates remained. The Premier bead mill was set up with0.6-0.8 mm zirconium oxide beads filling about 80% of the millingchamber. The bead mill was operated in accordance with themanufacturer's instructions at the settings listed in Table 1.

[0028] After milling, the particle size distribution of the suspensionsof Formulas 1-3 was measured using the Malvern laser diffraction unit.The sample was appropriately diluted, and the particle sizer wasoperated in accordance with the manufacturer's instructions at thesettings listed in Table 1. The results are reported in Table 1 asD(0.1), D(0.5), and D(0.9). D(0.1) represents the size (as numberaverage diameter) below which 10% of the particles lie, D(0.5) is thesize below which 50% of the particles lie, also known as the median.D(0.9) is the measurement below which 90% of the particles lie.

Examples of Bioenhanced Oral Solid Formulations

[0029] The milled suspension was spray dried using a laboratory scaleYamato GA-32 Spray Dryer. The spray dryer was operated in accordancewith the manufacturer's instructions at the settings listed in Table 1.In this apparatus, the milled aqueous suspension was fed by aperistaltic pump into the drying chamber as an atomized spray. Theresulting spray dried powder was further dried [for example, oven dryingat about 40° C.] to produce a dry powder composition which has goodflowability/ compactibility properties and hence, is suitable forfilling into hard gelatin capsules (Formulas 3-5 in Table 1).

[0030] The milled suspension was spray granulated in a fluid bedgranulator. The fluid bed contained the excipients listed in Table 2(Formulas 6 and 7). These granulations were blended with a disintegrantand a lubricant and compressed into pharmaceutically elegant tablets.

[0031] The spray dried material was further wet granulated using a highshear granulator and compressed into tablets by incorporating widelyused excipients (Formula 8 in Table 2).

Bio-Equivalence Studies

[0032] Test dogs were administered orally in a four-arm study using adose of 10 mg of eprosartan as zwitterion per kg. The internal granulesof the current product (refer to Table 3 for formulation details) wasused as the control.

[0033] Bio-equivalence studies to determine the relative bioavailabilityof oral bioenhanced formulations in healthy volunteers were performed.The study design comprised an open, randomised, and crossover. A singleoral 200 mg dose of the following formulations—a commercial tablet, acapsule of Formula 6 and a tablet of Formula 7. On each of the dosingdays subjects were to receive a single oral dose, with a washout of atleast 6 days between doses. Doses were administered orally with 200 mLwater, following a standard breakfast. The blood samples were collectedat predetermined time points and tested.

[0034] From the plasma concentration profiles obtained from the clinicalstudies both in dogs and humans, AUC_(max) (mg.hr/ml) [area under theplasma concentration vs. time curve], C_(max) (mg/ml) [maximum plasmaconcentration] and t_(max) (time in hours to achieve maximum plasmalevel) were calculated. The results, subjected to appropriatestatistical tests, showed an increase in blood levels by 2-5 fold, whendosing with capsules/tablets containing the bioenhanced formulations.TABLE 1 Bioenhanced Suspension Formulations Ingredients Nanoparticulatesuspension formulations % w/w Formula # 1 2 3 4 5 Eprosartan mesylate 1020 15.7 14.8 14.4 HPM cellulose 10 10 5.9 5.5 1.5 Mannitol 5.5 6.2Sodium lauryl sulfate Purified water to to to to to (ml) 100 100 100 100100 Parameter Bead milling conditions Bead size, mm 0.6-0.8 0.6-0.80.6-0.8 0.6-0.8 0.6-0.8 # passes 2 5 5 10 10 Parameter Malvern Particlesize Distribution D(0.1) in nm 181 123 117 98 101 D(0.5) in nm 759 671643 497 469 D(0.9) in nm 1200 1050 1097 893 879 Parameter Spray dryingconditions Inlet temp.(° C.) 125 125 125 Outlet temp.(° C.) 76 78-8478-84 Air flowrate 0.35 0.45 0.45 (m3/min) Atom. press (kg/cm2) 1.5 1.5Feed rate (ml/mm) 2 5 5

[0035] TABLE 2 Bioenhanced Tablet Formulations Ingredients mg/capsule ormg/tablet Formula 6-Capsule 7-Fluid bed 8-Highshear Bead milling Susp.Eprosartan mesylate 245.27 245.27 245.27 HPMC (Methocel E5) NF 91.9891.98 91.98 Silicon dioxide 5.01 5.01 5.01 Purified water USP * * *Fluid bed bulking ** Impalpable Lactose 57.74 47.74 47.74Microcrystalline cellulose 26.01 26 Crosslinked PVP USP 8 8 ExternalsCrosslinked PVP USP Magnesium stearate

[0036] TABLE 3 Formula of Eprosartan Commercial Product Ingredients %w/w Intragranular Eprosartan mesylate (400 mg as zwitterion)  61.32Lactose, Monohydrate (Impalpable) NF  3.59 Microcrystalline cellulose(Avicel PH102) NF  3.59 Pregelatinized starch (Starch 1551) USP  3.59Purified water USP  4.36* Extragranular Croscarmellose sodium(Ac-Di-Sol)  4.00 Microcrystalline cellulose (Avicel PH102) NF  19.Magnesium stearate NF  0.75 Tablet core weight (200 mg) 400.00 Filmcoating Opadry Blue OY-S-20900**

[0037] It is to be understood that the invention is not limited to theembodiments illustrated hereinabove and the right is reserved to theillustrated embodiments and all modifications coming within the scope ofthe following claims.

What is claimed is:
 1. A pharmaceutical composition comprisingeprosartan, or a salt, solvate, or hydrate thereof, in particulate form,said composition having a particle size distribution such that themedian value of the volume mean diameter is within the range of from 450to 700 nm.
 2. The composition according to claim 1 wherein eprosartan,or a salt, solvate, or hydrate thereof, is eprosartan mesylate.
 3. Thecomposition according to claim 1 which is produced by wet millingeprosartan, or a salt, solvate, or hydrate thereof, in the presence ofwater and pharmaceutically acceptable excipients.
 4. The compositionwherein the excipient is hydroxypropylmethyl cellulose or mannitol.
 5. Aprocess for the preparation of the composition according to claim 1 inwhich the eprosartan, or a salt, solvate, or hydrate thereof, inparticulate form, is produced by milling eprosartan, or a salt, solvate,or hydrate thereof, using a bead mill in the presence of hard zirconiumoxide beads, water and hydroxypropylmethyl cellulose, optionally addingone or more pharmaceutically acceptable excipients, spray drying andfilling the resulting powder into capsules.
 6. A method of blockingangiotensin II receptors which comprises administering to a subject inneed thereof an effective amount of the composition according toclaim
 1. 7. A method of treating hypertension which comprisesadministering to a subject in need thereof an effective amount of thecomposition according to claim
 1. 8. A method of treating congestiveheart failure which comprises administering to a subject in need thereofan effective amount of the composition according to claim
 1. 9. A methodof treating renal failure which comprises administering to a subject inneed thereof an effective amount of the composition according toclaim
 1. 10. A method of treating hypertension which comprisesadministering stepwise or in physical combination the compositionaccording to claim 1 and a second pharmaceutically active compoundselected from the group consisting of a diuretic, a calcium channelblocker, a β-adrenoceptor blocker, a renin inhibitor, and an angiotensinconverting enzyme inhibitor.
 11. The method according to claim 10wherein the second pharmaceutically active compound is a diuretic. 12.The method according to claim 11 wherein the diuretic ishydrochlorothiazide.
 13. The use of a composition according to claim 1for the treatment of diseases in which blockade of the angiotensin IIreceptor is indicated.
 14. The use of a composition according to claim 1for the treatment of hypertension.
 15. The use of a compositionaccording to claim 1 for the treatment of congestive heart failure. 16.The use of a composition according to claim 1 for the treatment of renalfailure.
 17. The use of a composition according to claim 1 incombination with a diuretic for the treatment of hypertension.
 18. Theuse according to claim 17 wherein the diuretic is hydrochlorothiazide.